1,4-diazabicyclo[3.2.2]nonane-4-carboxylates and carboxamide derivates, production and use thereof in therapeutics

ABSTRACT

Compounds of general formula                  
 
in which X represents an oxygen atom or a group of formula NZ in which Z represents a hydrogen atom or an alkyl group, n represents a number 0, 1 or 2, and R 1 , R 2 , R 3 , R 4  and R 5  each represent a hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, alkyl, alkoxy, phenoxy or phenyl group optionally substituted with a halogen atom or a trifluoromethyl, cyano, hydroxyl, alkyl or alkoxy group, or alternatively R 2  and R 3  together form a group of formula —OCH 2 O— or —CH 2 CH 2 CH 2 CH 2 —.
 
Application in therapy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. §371 application of PCT Internationalapplication No. PCT/FR00/00697, filed Mar. 21, 2000.

The subject of the present invention is compounds of general formula (I)

in which

-   X represents an oxygen atom or a group of formula NZ in which Z    represents a hydrogen atom or a (C₁–C₆)alkyl group,-   n represents a number 0, 1 or 2, and-   R₁, R₂, R₃, R₄ and R₅ each represent, independently of each other, a    hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy,    cyano, hydroxyl, (C₁–C₆) alkyl, (C₁–C₆) alkoxy, phenoxy or phenyl    group optionally substituted with a halogen atom or a    trifluoromethyl, cyano, hydroxyl, (C₁–C₆)alkyl or (C₁–C₆)alkoxy    group, or alternatively R₂ and R₃ together form a group of formula    —OCH₂O— or —CH₂CH₂CH₂CH₂—.

The compounds of the invention may exist in the form of bases or ofaddition salts with acids.

To prepare the compounds of general formula (I),1,4-diazabicyclo[3.2.2]nonane may be reacted with a compound of generalformula (II)

in which n, R₁, R₂, R₃′ R₄ and R₅ are as defined above, X′ represents anoxygen atom or a group of formula N-alkyl and Y represents a halogenatom, in the presence of a base such as triethylamine or pyridine.

To prepare the compounds of general formula (I) in which X represents anNH group, it is possible to react 1,4-diazabicyclo[3.2.2]nonane with anisocyanate of general formula (III)

in which n, R₁, R₂, R₃, R₄ and R₅ are as defined above, under conditionsidentical to those described above.

1,4-Diazabicyclo[3.2.2]nonane is described in J. Med. Chem. (1993) 362311–2320.

The compounds of general formulae (II) and (III) are commerciallyavailable or may be prepared according to any known methods.

The examples which follow illustrate the preparation of a few compoundsof the invention. The elemental microanalyses, and the IR and NMRspectra confirm the structures of the compounds obtained. The numbersindicated in brackets in the titles of the examples correspond to thoseof the 1^(st) column of the table given later.

In the names of the compounds, the hyphen “-” is part of the word, andthe underscore “_(—)” serves only for the break at the end of the line;it should be removed in the absence of a break, and should not bereplaced either by a normal hyphen or by a space.

EXAMPLE 1 Compound No. 2 4-Bromophenyl1,4-diazabicyclo[3.2.2]nonane-4-carboxylate.

0.379 g (3.0 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 0.84 ml (6.0mmol) of triethylamine in 5 ml of dichloromethane are introduced into a50-ml three-necked flask, the mixture is cooled to 0° C., 0.730 mg (3.1mmol) of 4-bromophenyl chloroformate in solution in 3 ml ofdichloromethane is added dropwise and the stirring is maintained at 0°C. for 10 min.

The reaction medium is washed with water, the aqueous phase is washedtwice with dichloromethane, the combined organic phases are washed witha saturated aqueous sodium chloride solution, dried and the solvent isevaporated off under reduced pressure. The residue obtained is purifiedby silica gel chromatography, eluting with a 95/5/0.5 mixture ofchloroform, methanol and aqueous ammonia. A crude product is obtainedwhich is triturated in diisopropyl ether.

0.77 g of pure product is thus obtained in the form of a white solid.

Melting point 115–116° C.

EXAMPLE 2 Compound No. 8N-Phenyl-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide hydrobromide (1:1).

0.378 g (3.0 mmol) of 1,4-diazabicyclo[3.2.2]nonane in solution in 10 mlof acetonitrile is introduced into a 25-ml three-necked flask, asolution of 0.358 g (3.0 mmol) of isocyanatobenzene in 2 ml ofacetonitrile is added at 3° C. and the reaction medium is stirred for 10min at room temperature.

The solvent is evaporated off under reduced pressure in order to obtaina solid which is dissolved in 30 ml of ethanol and which is treated with0.53 ml of a 5.7 M hydrobromic acid solution in acetic acid at 50° C.The precipitate which forms is filtered and it is washed twice withethanol.

0.649 g of product is thus obtained in the form of a white solid.

Melting point: 229–231° C.

EXAMPLE 3 Compound No. 10N-Methyl-N-phenyl-1,4-diazabicyclo[3.2.2]_(—)nonane-4-carboxamidehydrobromide (1:1).

0.69 ml (1.31 mmol) of a 20% solution of phosgene in toluene diluted byaddition of 4 ml of toluene is introduced into a 25-ml three-neckedflask (1.31 mmol) and the solution is cooled to 0° C. A solution of0.127 g (1.12 mmol) of N-methylaniline and 0.11 ml of pyridine in 4 mlof toluene is added over 10 min and the mixture is kept magneticallystirred for 30 min at 0° C.

10 ml of ice-cold water are added and the organic phase is separated. Ina 25-ml three-necked flask, this solution is poured over a suspensioncontaining 0.15 g (1.12 mmol) of 1,4-diazabicyclo[3.2.2]nonane in 0.11ml of pyridine and the mixture is stirred for 30 min.

10 ml of chloroform are added, the solution obtained is washed with 15ml of a 1 M aqueous sodium hydroxide solution, the solvent is evaporatedoff and the residue is purified by silica gel chromatography, elutingwith a 95/5/0.5 mixture of chloroform, methanol and diethylamine.

0.31 g of product is obtained which is taken up in 5 ml of ethanol,0.109 ml of an aqueous hydrobromic acid solution is added, the medium isdiluted with addition of 5 ml of diisopropyl ether and the precipitateis recovered by filtration.

0.387 g of product is thus obtained in the form of a white solid.

Melting point: 292–293° C.

EXAMPLE 4 Compound No. 11

[1,1′-Biphenyl-4-yl]1,4-diazabicyclo[3.2.2]nonane-4-carboxylatehydrobromide (1:1).

4.1. [1,1′-Biphenyl-4-yl]chloroformate. Preparation according to themethod described in Bull. Soc. Chim. Fr. (1967).

2.00 g (11.75 mmol) of [1,1′-biphenyl]-4-ol in suspension in 50 ml ofdichloromethane are introduced into a 50-ml three-necked flask, 0.47 g(11.75 mmol) of 60% sodium hydride in mineral oil is added portionwise,and the solvent is evaporated off under reduced pressure. A white solidis obtained which is added over 1 h to 6.84 ml (12.92 mmol) of a 20%solution of phosgene in toluene at 30° C. and left in contact for 3 h.

The solvent is evaporated off under reduced pressure, the residue istriturated in petroleum ether, filtered to remove the minerals and thesolvent is evaporated off under reduced pressure.

0.89 g of crude product is thus obtained.

Melting point: 36° C.

4.2. [1,1′-Biphenyl-4-yl]1,4-diazabicyclo[3.2.2]nonane-4-carboxylatehydrobromide (1:1).

0.15 g (1.19 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 0.33 ml (2.38mmol) of triethylamine in solution in 10 ml of chloroform are introducedinto a 50-ml three-necked flask, the mixture is cooled to 0° C. and thenthe chloroformate previously obtained in solution in 10 ml of chloroformis added over 10 min. The mixture is stirred at 0° C. for 10 min beforeallowing the temperature to rise to ambient temperature and it is leftat room temperature for 18 h.

15 ml of 1 M sodium hydroxide are added and the mixture is extractedwith chloroform. The solvent is evaporated off under reduced pressureand the residue obtained is purified by silica gel chromatography,eluting with a 98/2/0.2 and then 96/4/0.4 mixture of chloroform,methanol and diethylamine.

0.31 g of product is obtained which is dissolved in 5 ml of ethanol, thesolution is treated with 0.109 ml (0.96 mmol) of an aqueous hydrobromicacid solution, 5 ml of diisopropyl ether are added and the precipitateis filtered.

0.387 g of product is thus obtained in the form of a white solid.

Melting point 292–293° C.

The table which follows illustrates the chemical structures and thephysical properties of some compounds of the invention.

In the “Salt” column, “-” denotes a compound in the form of a base,“HBr” denotes a hydrobromide and “ox” denotes an oxalate, orethanedioate; the acid:base molar ratio is indicated adjacent thereto.

TABLE

No. X n R₁ R₂ R₃ R₄ R₅ Salt m.p. (° C.) 1 O 0 H H Cl H H — 109–110 2 O 0H H Br H H — 115–116 3 O 0 H H CH₃ H H — 92–93 4 O 0 H H OCH₃ H H — 83.55 O 0 H H H H H HBr 1:1 239–240 6 O 0 H H NO₂ H H — 98   7 O 0 H H F H H— 66–68 8 NH 0 H H H H H HBr 1:1 229–231 9 O 1 H H H H H HBr 1:1175.5–176   10 NCH₃ 0 H H H H H HBr 1:1 206–207 11 O 0 H H C₆H₅ H H HBr1:1 292–293 12 O 0 Br H H H H — 87–88 13 O 0 CH₃ H H H H ox 1:1 164–16614 O 0 H CH₃ H H H ox 1:1 164–166 15 O 0 H OCH₃ H H H ox 1:1 152–154 16O 0 H CF₃ H H H ox 1:1 95–96 17 O 0 H OCH₂O H H — 123–124 18 O 0 OCH₃ HH H OCH₃ — 130–131 19 O 0 H F F H H ox 1:1 171–173 20 O 0 H Cl Cl H H ox1:1 174–178 21 O 0 H H OCF₃ H H ox 1:1 204–205 22 O 0 H CH₂CH₂CH₂CH₂ H Hox 1:1 202–203 23 O 0 H H OC₆H₅ H H — 107–108

The compounds of the invention were the subject of trials whichdemonstrated their therapeutic properties.

The compounds of the invention were also studied in relation to theiraffinity towards the nicotinic receptors containing the α7 subunit,according to the methods described by Marks and Collins, J. Pharmacol.Exp. Ther. (1982) 22 554 and Marks et al., Mol. Pharmacol. (1986) 30427.

150- to 200-g male rats are decapitated, the whole brain is rapidlycollected, homogenized with the aid of a Polytron™ grinder in 15 volumesof a 0.32 M sucrose solution, and then it is centrifuged at 1000 g for10 min. The pellet is removed and the supernatant is centrifuged at 8000g for 20 min at 4° C. The pellet is recovered and homogenized with theaid of a Polytron™ grinder in 15 volumes of double-distilled water at 4°C., and then it is centrifuged at 8000 g for 20 min. The pellet isremoved and the supernatant and the buffy coat are centrifuged at 40,000g for 20 min. The pellet is recovered, it is resuspended with 15 volumesof double-distilled water at 4° C. and it is again centrifuged once at40,000 g for 20 min before being stored at −80° C.

On the day of the experiment, the tissue is thawed slowly and it issuspended in 5 volumes of buffer. 150 μl of this membrane suspension arepreincubated at 37° C. for 30 min, in the dark, in the presence orabsence of the test compound. The membranes are then incubated for 60min at 37° C., in the dark, in the presence of 50 μl of 1 nM[³H]a-bungarotoxin in a final volume of 250 μl of 20 mM HEPES buffercontaining 0.05% of polyethylenimine. The reaction is stopped byfiltration on Whatman GF/C™ filters previously treated for 3 hours with0.5% polyethylenimine. The filters are rinsed with twice 5 ml of bufferat 4° C., and the radioactivity retained on each filter is measured byliquid scintigraphy. The non-specific binding is determined in thepresence of α-bungarotoxin at 1 μM final; the non-specific bindingrepresents about 60% of the total binding recovered on the filter. Foreach concentration of compound studied, the percentage inhibition of thespecific binding of [³H]α-bungarotoxin is determined and then the IC₅₀,the concentration of compound which inhibits the specific binding by50%, is calculated.

The IC₅₀ values for the compounds of the invention which have thehighest affinity are between 0.04 and 0.5 μM.

The results of the preceding trials show that the compounds of theinvention are ligands for the α₇ subunits of the nicotinic receptor.

These results suggest the use of the compounds in the treatment orprevention of disorders linked to nicotinic receptor dysfunction, inparticular at the level of the central nervous system or of thegastrointestinal system.

At the level of the central nervous system, these disorders comprisecognitive impairments, more particularly memory impairments, but alsoattention impairments, linked to Alzheimer's disease, to pathologicalageing (Age Associated Memory Impairment, AAMI), to Parkinson'ssyndrome, to trisomy 21 (Down's syndrome), to Korsakoff's alcoholicsyndrome, to vascular dementia (multi-infarct dementia, MID).

The compounds of the invention could also be useful in the treatment ofthe motor disorders observed in Parkinson's disease or otherneurological diseases such as Huntington's chorea, Tourette's syndrome,tardive dyskinesia and hyperkinesia.

The compounds of the invention may also constitute a curative orsymptomatic treatment of cerebrovascular accidents and of cerebralhypoxic episodes.

They may be used in the case of psychiatric pathologies: schizophrenia,depression, anxiety, panic attacks or obsessive-compulsive behaviour.

They can prevent the symptoms due to withdrawal from tobacco, fromalcohol and from various substances which induce dependence, such ascocaine, LSD, cannabis, benzodiazepines.

At the level of the gastrointestinal system, the compounds of theinvention could be useful in the treatment of Crohn's disease,ulcerative colitis, irritable bowel syndrome and obesity.

To this end, the compounds of the invention may be provided in any formsof compositions appropriate for enteral, parenteral or transdermaladministration, such as tablets, sugar-coated tablets, hard gelatinecapsules, soft gelatine capsules, oral or injectable suspensions orsolutions such as syrups or ampoules, transdermal patches and the like,combined with suitable excipients, and containing doses to allow a dailyadministration of 0.01 to 20 mg/kg.

1. A compound corresponding to the formula (I)

in which X represents an oxygen atom or a group of formula NZ in which Zrepresents a hydrogen atom or a (C₁–C₆)alkyl group, n represents anumber 0, 1 or 2, and R₁, R₂, R₃, R₄ and R₅ each represent,independently of each other, a hydrogen or halogen atom or atrifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (C₁–C₆)alkyl,(C₁–C₆)alkoxy, phenoxy or phenyl group optionally substituted with ahalogen atom or a trifluoromethyl, cyano, hydroxyl, (C₁–C₆)alkyl or(C₁–C₆)alkoxy group, or alternatively R₂ and R₃ together form a group offormula OCH₂O— or —CH₂CH₂CH₂CH₂—, in the form of a base or of anaddition salt with an acid.
 2. A pharmaceutical composition comprising acompound according to claim 1, combined with an excipient.
 3. A methodfor the treatment of Alzheimer's disease or schizophrenia whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 1. 4.4-Bromophenyl-1,4-diazabicyclo[3.2.2]nonane-4-carboxylate according toclaim
 1. 5. A pharmaceutical composition comprising a compound accordingto claim 4, combined with an excipient.
 6. A method for the treatment ofAlzheimer's disease or schizophrenia which comprises administering to apatient in need of such treatment an effective amount of a compoundaccording to claim 4.